Imidazoyl-substituted thiomethylpyridine derivatives, method of administration thereof and medicaments containing them

ABSTRACT

Thiomethylpyridine derivatives having bronchosecretolytic and mucolytic activity according to the formula: ##STR1## wherein R is a group attached in the 2-, 3- or 4-position of the pyridine ring which corresponds to the following general formula: 
     
         Q--S--CH.sub.2 --                                          (II) 
    
      wherein Q is a substituted or unsubstituted aryl group or a 5- or 6-membered heterocyclic group which may optionally contain one or more substituents and/or which may be condensed with an optionally substituted phenyl group or with an optionally substituted heterocycle; 
     R&#39; is a lower alkyl group, a halogen atom or an aminoalkyl group; and 
     n is 0 or an integer of from 1 to 4; 
     and the therapeutically-acceptable acid addition salts thereof. 
     The new compounds are distinguished by surprising activity compared with known compounds, such as &#34;Ambroxol&#34;.

This application is a continuation of application Ser. No. 797,113,filed Nov. 12, 1985, now abandoned, which in turn is a divisional ofapplication Ser. No. 490,138, filed Apr. 29, 1983, now abandoned.

This invention relates to new thiomethyl pyridine derivatives, to aprocess for their production and to medicaments containing them.

The new compounds according to the invention are surprisinglydistinguished by high bronchosecretolytic and mucolytic activity whichmay be therapeutically utilized.

It is well known that reducing the viscosity of sputum by medicaments inthe treatment of acute and chronic bronchial illnesses (for exampleinfections of the respiratory tracts, asthmatic complaints, obstructivedisorders and the like) is an important therapeutic objective. Variouskinds of medicaments are known for treating illnesses of this kind. Theydiffer from one another in their local and systemic activity. N-acetylcysteine inter alia belongs to the group of locally active medicaments.The systemically active types include for example Ambroxol, i.e.trans-4-(2-amino-3,5-dibromobenzyl)-aminocyclohexanol, which is anestablished bronchosecretolytic agent in the treatment of bronchialdisease. This compound is described, for example, in German Pat. No.1,593,579.

The object of the present invention is to provide newbronchosecretolytically and mucolytically a ctive compounds of which theoral and parenteral activity is significantly improved in relation toestablished compounds acting in the same direction, such as for exampleAmbroxol.

This object is achieved by the invention.

Accordingly, the present invention relates to new thiomethyl pyridinederivatives corresponding to the following general formula ##STR2## inwhich R is a group attached in the 2-, 3- or 4-position of the pyridinering and corresponding to the following general formula

    Q--S--CH.sub.2 --                                          (II)

where Q is a substituted or unsubstituted aryl group or a 5- or6-membered heterocyclic group which may optionally be substituted by oneor more substituents and/or which may be condensed with an optionallysubstituted phenyl group or an optionally substituted heterocycle,

R' is a lower alkyl group, a halogen atom or an aminoalkyl group and

n=0 to 4,

and to their therapeutically acceptable acid addition salts.

In general formula I, R is a group attached in the 2-, 3- or 4-positionof the pyridine ring and corresponding to the following formula

    Q--S--CH.sub.2 --                                          (II)

in which Q is an aryl group, for example a phenyl or naphthyl group. Thearyl group may be unsubstituted or substituted by one or moresubstituents, such as halogen atoms, lower alkyl groups or lower alkoxygroups. Halogen atoms are, for example, fluorine atoms, chlorine atoms,bromine atoms and iodine atoms, chlorine atoms being preferred. Loweralkyl groups are straight-chain or branched-chain alkyl groupscontaining from 1 to 4 carbon atoms, such as for example methyl groups,ethyl groups, isopropyl groups and butyl groups. Lower alkoxy groupscontain from 1 to 4 carbon atoms in the alkyl chain. Examples of loweralkoxy groups are methoxy groups, ethoxy groups, propoxy groups andbutoxy groups. One preferred example of a substituted aryl group is aphenyl group which is substituted in the p-position by a halogen atom,preferably a chlorine atom, by a lower alkyl group, preferably a methylgroup, or by a lower alkoxy group, preferably a methoxy group.

In addition, Q may be a 5- or 6-membered heterocyclic group which may besubstituted by one or more substituents and/or which may be condensedwith an optionally substituted phenyl group or an optionally substitutedheterocycle. Practical examples of a heterocyclic group such as this arethe imidazolyl group, thiazolyl group, thienyl group, oxazolyl group,pyrimidinyl group or pyridyl group. The heterocyclic group may containone or more substituents. Examples of the substituents in question arelower alkyl groups, halogen atoms and alkoxy groups. Lower alkyl groupsare linear or branched carbon chains containing from 1 to 4 carbonatoms, such as for example methyl groups, ethyl groups, isopropyl groupsor butyl groups. Halogen atoms are, for example, fluorine atoms,chlorine atoms, bromine atoms and iodine atoms. Lower alkoxy groups aremethoxy groups, ethoxy groups, propoxy groups and butoxy groups.

The 5- or 6-membered heterocyclic group may in addition be condensedwith an optionally substituted phenyl group or an optionally substitutedheterocycle. The optionally substituted heterocycle may be, for example,pyridine, pyrimidine or thiazole. The phenyl group and the heterocyclemay be substituted, preferably by a halogen atom, preferably a chlorineatom, by a lower alkyl group, preferably a methyl group, or by a loweralkoxy group, preferably a methoxy group.

As mentioned above, the group R may be attached in the 2-, 3- or4-position of the pyridine ring, the 3-position being preferred.

In general formula I, R' is a lower alkyl group (as defined above), ahalogen atom (as described above) or an aminoalkyl group (the alkylgroup preferably being a lower alkyl group). n has a value of from 0 to4. Where n=0, the pyridine ring, apart from the substituent R, isunsubstituted. Where n=1, the pyridine ring carries a substituent R'which is preferably attached in the 6-position of the pyridine ring.Where n=2, two groups R' are present, preferably being attached in the5-position and 6-position of the pyridine ring. As for the rest, thepyridine ring may be substituted by the radical R' irrespective of theposition of the nitrogen atom.

The compounds corresponding to general formula I readily form acidaddition salts, for example mono-, di- and tri-addition salts, such asfor example hydrochlorides, hydrobromides, sulfates, acetate, maleates,fumarates, oxalates, succinates and embonates, etc.

The compounds according to the invention may be produced by a processwhich is characterized in that, using methods known per se, a thiolatecorresponding to the following general formula

    Q--SMe                                                     (III)

in which Q is as defined above and Me is an alkali atom, is reacted witha picolyl chloride hydrohalide corresponding to the following generalformula ##STR3## in which Hal is a halogen atom and in which thechloromethyl group is in the 2-, 3- or 4-position of the pyridine ringand R' and n are as defined above, in an aqueous-alcoholic alkalihydroxide solution in which the alkali hydroxide is present in an excessover and above the stoichiometric quantity and the free base thusobtained is optionally converted into a therapeutically acceptable acidaddition salt.

In formula III, Me is an alkali atom, for example a potassium or sodiumatom, a sodium atom being preferred. In general formula IV, Hal is ahalogen atom, for example a chlorine or bromine atom, preferably achlorine atom. The reaction is carried out in an aqueous-alcoholicalkali hydroxide solution in which the alkali hydroxide is present in anexcess over and above the stoichiometric quantity, preferably in atleast twice the equimolar quantity. The aqueous-alcoholic solution ispreferably an aqueous-ethanolic solution. The preferred alkali hydroxideis sodium hydroxide. The reaction is best carried out by dissolving thethiolate corresponding to general formula III in the aqueous-alcoholicalkali hydroxide solution at a temperature of from 0° to 5° C. andsubsequently reacting the resulting solution for 2 to 6 hours andpreferably for 4 hours at room temperature with an equimolar quantity ofthe picolyl chloride hydrohalide compound dissolved in aqueous-alcoholicand preferably aqueous-ethanolic solution.

Because the alkali hydroxide is used in a stoichiometric excess, thefree base is obtained and may be subsequently converted into atherapeutically acceptable salt in the usual way by reaction with apharmaceutically acceptable acid.

The compounds according to the invention are distinguished by asurprisingly improved bronchosecretolytic and mucolytic activity so thatthey may be used for therapy in considerably smaller quantities thanknown active substances.

Accordingly, the present invention also relates to a pharmaceuticalpreparation or medicament having bronchosecretolytic and mucolyticactivity which, in addition to standard auxiliaries and vehicles,contains at least one thiomethyl pyridine derivative corresponding togeneral formula I.

The pharmaceutical preparation according to the invention may be usedfor all types of bronchial illness, for example actute and chronicrespiratory disease, for post-operative treatment of the respiratorytracts and also in all processes where it is desirable to reduce theviscosity of bronchial mucus.

The compound used in accordance with the invention is preferably orallyadministered. The oral daily dose usually amounts to be between 0.01 and0.2 g and preferably to between 0.02 and 0.1 g which may be administeredin one or more daily doses. It may be necessary in individual cases toadminister larger or smaller doses in dependence upon the reaction ofthe individual to the active substance or its formulation and to thetime at which or period over which it is administered. For example,there are cases where the compound used in accordance with the inventionmay be effectively administered in less than the minimum quantityindicated above, whereas in other cases the upper limit specified has tobe exceeded. In cases where relatively large quantities areadministered, it may be advisable to divide them into several individualdoses for daily administration.

For oral administration, the active substance may be formulated forexample as capsules produced by conventional methods usingpharmaceutically acceptable excipients, for example binders (such aspregelatinized cornstarch, polyvinyl pyrrolidone or hydroxy propylmethylcellulose); fillers (such as lactose, microcrystalline cellulose orcalcium phosphate); lubricants (such as magnesium stearate, talcum orsilica); disintegrating agents (for example potato starch or sodiumstarch glycolate); or moistening agents (for example sodium laurylsulfate). The capsules may be coated by known methods. Liquidpreparations for oral administration or for direct instillation mayassume the form of solutions, syrups or suspensions for example or maybe presented as a dry product for reconstitution before use either withwater or with any other suitable vehicle. Liquid preparations such asthese may be prepared by conventional methods using pharmaceuticallyacceptable additives, for example suspending agents (such as sorbitolsyrup, methyl cellulose or hydrogenated edible fats); emulsifiers (forexample lecithin or acacia); nonaqueous vehicles (for example almondoil, oily esters or ethyl alcohol); and preservatives (for examplemethyl- or propyl-p-hydroxybenzoates or sorbic acid).

For buccal administration, the preparations may be presented in the formof tablets or lozenges formulated in the usual way.

The compound used in accordance with the invention may be formulated forparenteral administration by injection or for infusion. Preparations forinjection may be presented in unit dose form, for example in ampoules orin multi-dose containers, with an added preservative. The preparationsmay also assume such forms as suspensions, solutions or emulsions inoily or aqueous vehicles and may contain formulating agents, such assuspending agents, stabilizing agents and/or dispersants. Alternatively,the active substance may even be presented in powder form forreconstitution before use with a suitable vehicle, for example sterile,pyrogen-free water.

For administration by inhalation, the compound according to theinvention is suitably applied in the form of an aerosol spray frompressurized packs or atomizers using a suitable propellent, for exampledichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, carbon dioxide or any other suitable gas. Inthe case of a pressurized aerosol, the unit dose may be determined bythe provision of a valve for releasing a measured quantity.

Pharmacological studies have shown that the thiomethyl pyridinederivatives used in accordance with the invention have superiorbronchosecretolytic and mucolytic properties to the known comparisonproduct, Ambroxol. The following individual studies were carried out:

1. Pharmacodynamics

1.1 Secretostimulating activity

Bronchosecretolytically active compounds promote the tracheal secretionof phenol red (Chronic Bronchitis Research Group, Chinese MedicalJournal 3: 259, 1977). The increase in the tracheal secretion of phenolred is a measure of bronchosecretolytic activity. The relevant activityof the test substances was studied after oral administration tonon-anaesthetized mice. The ED₅₀ -values indicated in Table I werecalculated using the regression curves. As can be seen from the Table,2-(pyridyl-3-methylthio)-pyrimidine hydrochloride showed the strongestactivity. Its effect in promoting the secretion of phenol red wasapproximately 160 times stronger than that of the knownbronchosecretolytic, Ambroxol.

                  TABLE I    ______________________________________    Compound       ED.sub.50 (mg/kg)    ______________________________________    Ambroxol       250    Example 1      1.5    Example 2      400    Example 7      15    Example 9      45    Example 8      15    Example 5      2.1    Example 6      6.3    Example 3      10    Example 4      12    Example 10     12    ______________________________________

1.2 Mucosecretolytic activity in dogs

Bronchial mucus was removed by means of a bronchoscope fromanaesthetized mongrel dogs immediately before and 1 hour afterintravenous administration of the test substances and taken up inphosphate buffer. After dialyzation and freeze-drying, the mucus sampleswere taken up in 0.1M tris-buffer (pH 7) (final concentration 1% w/v).Viscosity was measured by means of a rotary viscosimeter (asmanufactured by Contraves, Stuttgart).

As can be seen from Table II, the known bronchosecretolytic, Ambroxol,produced a distinct reduction in the viscosity of the bronchial mucus.The identical quantity by weight of 2-(pyridyl-3-methylthio)-pyrimidinehydrochloride produced an even more distinct reduction in the viscosityof the bronchial mucus.

                  TABLE II    ______________________________________            Dose and   Viscosity mPa × s              administration                           Initial  1 hour after    Compound  route        value    administration    ______________________________________    Control   i.v.         4.2      4.8    (0.9% of NaCl)         (3.6-4.8)                                    (4.4-5.2)    Example 1 10 mg/kg i.v.                           3.9      1.2                           (3.2-4.5)                                    (1.0-1.4)    Ambroxol  10 mg/kg i.v.                           3.8      2.3                           (3.6-4.0)                                    (1.4-3.2)    ______________________________________

2. Toxicologic results

The compounds according to the invention show low oral toxicity in acutetests. Thus, 2-(pyridyl-3-methylthio)-pyrimidine hydrochloride was foundto have an LD₅₀ -value in mice of 1156 mg/kg p.o. Under identicalconditions, Ambroxol proved to be slightly less toxic (LD₅₀ : 2720 mg/kgp.o according to Puschmann et al, Arzn. Forsch. 28: 889, 1978).

The invention is illustrated by the following Examples.

EXAMPLE 1 Production of 2-(pyridyl-3-methylthio)-pyrimidinehydrochloride ##STR4##

8.4 g (0.21 mole) of sodium hydroxide dissolved in 120 ml of water areadded dropwise at 0° C. to a solution of 11.2 g (0.1 mole) of2-mercaptopyrimidine in 250 ml of ethanol. 16.4 g (0.1 mole) of3-picolyl chloride hydrochloride dissolved in 100 ml of water are thenslowly added, followed by stirring for 4 hours at room temperature. Thereaction solution is concentrated, taken up in 500 ml of ether, theorganic phase is washed 3 times with 100 ml of water, dried over sodiumsulfate, filtered and the filtrate concentrated in vacuo. The solidaccumulating, which represents the base, is recrystallized from hexane.

Colorless crystals melting at 53° to 54° C.; R_(f) =0.5 (CH₂ Cl₂/MeOH9/1); Yield 9.14 g (45%) C₁₀ H₉ N₃ S (203) calculated: C 59.09 H4.46 N 20.67 S 15.77 observed: C 59.20 H 4.47 N 20.65 S 15.73

¹ H-NMr-spectrum (CDCl₃): δ=4.40 (s) (--SCH₂ --)2H, 7.0 (t)(aromatics-H) 1H, 7.20 (m) (aromatics-H) 1H, 7.80 (d) (aromatics-H) 1H,8.53 (m) (aromatics-H) 3H, 8.73 (s) (aromatics-H) 1H ppm

The hydrochloride is prepared by adding an equimolar 10% ethanolicHCl-solution to an ethereal solution of2-(pyridyl-3-methylthio)-pyrimidine. The hydrochloride accumulates inanalytically pure form.

Colorless crystals melting at 134° to 135° C.; R_(f) =0.85 (CH₂ Cl₂/MeOH, 8/2, NH₃ -vapors); Yield (quant.) C₁₀ H₁₀ ClN₃ S (240)calculated: C 50.10 H 4.20 N 17.53 S 13.37 observed: C 50.18 H 4.10 N17.45 S 13.36

¹ H-NMR-spectrum (D₂ O): δ=5.03 (s) (--S--CH₂) 2H, 7.70 (t)(aromatics-H) 1H, 8.43 (m) (aromatics-H) 1H, 9.03 (d) (aromatics-H) 2H,9.13 (t) (aromatics-H) 2H, 9.37 (s) (aromatics-H) 1H ppm

EXAMPLE 1a Production of 2-(pyridyl-3-methylthio)-pyrimidine succinate

The succinate is prepared by adding an equimolar ethanolic succinic acidsolution to an ethanolic solution of2-(pyridyl-3-methylthio)-pyrimidine. After concentration of the reactionsolution, the succinate accumulates in analytically pure form.

Colorless crystals melting at 98° C.; R_(f) =0.78 (CH₂ Cl₂ /MeOH8/2, NH₃-vapors); Yield: (quant.) C₁₄ H₁₅ N₃ O₄ S (321) calculated: C 52.33 H4.71 N 13.08 S 9.98 observed: C 52.31 H 4.78 N 13.06 S 9.92

¹ H-NMR-spectrum (d₆ -DMSO) δ=2.40 (s) (--CH₂ --CH₂ --) 4H, 4.43 (s)(S--CH₂) 2H, 7.27 (t) (aromatics-H) 1H, 7.37 (m) (aromatics-H) 1H, 7.87(d) (aromatics-H) 1H, 8.47 (d) (aromatics-H) 1H, 8.67 (m) (aromatics-H)3H ppm.

EXAMPLE 2 Production of 2-(pyridyl-2-methylthio)-pyrimidinehydrochloride ##STR5##

This compound is produced as in Example 1 from 2-mercaptopyrimidine and2-picolyl chloride hydrochloride.

Colorless crystals melting at 163° to 164° C.; R_(f) =0.85 (CH₂ Cl₂/MeOH, 8/2, NH₃ -vapors); Yield 14.3 g (60%) C₁₀ H₁₀ ClN₃ S (240)calculated: C 50.10 H 4.20 N 17.53 S 13.37 observed: C 50.02 H 4.23 N17.39 S 13.54

¹ H-NMR-spectrum (D₂ O): δ=5.13 (s) (S--CH₂) 2H, 7.67 (t) (aromatics-H)1H, 8.37 (t) (aromatics-H) 1H, 8.53-9.27 (m) (aromatics-H) 5H ppm

EXAMPLE 3 Production of 2-(pyridyl-3-methylthio)-4-methyl-pyrimidinehydrochloride ##STR6##

This compound is produced as in Example 1 from 2-mercapto-4-methylpyrimidine and 3-picolyl chloride hydrochloride.

Colorless crystals melting at 154° C.; R_(f) =0.8 (CH₂ Cl₂ /MeOH, 8/2,NH₃ -vapors); Yield 10.9 g (43%) C₁₁ H₁₂ ClN₃ S (254) calculated: C52.07 H 4.77 N 16.56 S 12.63 observed: C 52.18 H 4.81 N 16.58 S 12.55

¹ H-NMR-spectrum (D₂ O): δ=2.80 (2) (CH₃) 3H, 4.93 (s) (S--CH₂) 2H, 7.43(d) (aromatics-H) 1H, 8.47 (t) (aromatics-H) 1H, 8.73 (d) (aromatics-H)1H,9.17 (m) (aromatics-H) 2H, 9.47 (s) (aromatics-H) 1H ppm.

EXAMPLE 4 Production of 2-(pyridyl-3-methylthio)-4,6-dimethyl-pyrimidinehydrochloride ##STR7##

This compound is produced as in Example 1 from4,6-dimethyl-2-mercaptopyrimidine and 3-picolyl chloride hydrochloride.

Colorless crystals melting at 155° to 156° C.; R_(f) =0.8 (CH₂ Cl₂/MeOH, 8/2, NH₃ -vapors); Yield 10.2 g (38%) C₁₂ H₁₄ ClN₃ S (268)calculated: C 53.83 H 5.27 N 15.69 S 11.97 observed: C 53.79 H 5.37 N15.70 S 11.93

¹ H-NMR-spectrum (D₂ O): δ=2.73 (s) (2×CH₃) 6H, 4.90 (s) (S--CH₂) 2H,7.20 (s) (aromatics-H) 1H, 8.43 (t) (aromatics-H) 1H, 8.83 (d)(aromatics-H) 2H, 9.13 (s) (aromatics-H) 1H ppm

EXAMPLE 5 Production of 2-(pyridyl-3-methylthio)-pyridinedihydrochloride ##STR8##

This compound is produced as in Example 1 from 2-mercaptopyridine and3-picolyl chloride hydrochloride.

Colorless crystals melting at 149° to 152° C.; R_(f) =0.75 (CHCl₃ /C₂ H₅OH, 8/2, NH₃ -vapors); Yield 5.9 g (25%) C₁₁ H₁₂ Cl₂ N₂ S (239)calculated: C 48.16 H 4.38 S 11.68 observed: C 48.28 H 4.32 S 11.53

¹ H-NMR-spectrum (D₂ O): δ=5.30 (s) (S--CH₂) 2H, 8.13-9.33 (aromatics-H)7H, 9.50 (s) (aromatics-H) 1H ppm

EXAMPLE 6 Production of 2-(pyridyl-2-methylthio)-pyridinedihydrochloride ##STR9##

This compound is produced as in Example 1 from 2-mercaptopyridine and2-picolyl chloride hydrochloride.

Colorless crystals melting at 106° to 108° C.; R_(f) =0.75 (CHCl₃ /C₂ H₅OH, 8/2, NH₃ -vapors); Yield 6.7 g (28%) C₁₁ H₁₂ Cl₂ N₂ S (239)calculated: C 48.16 H 4.38 S 11.68 observed: C 45.99 H 4.71 S 11.04

¹ H-NMR-spectrum (D₂ O): δ=5.37 (s) (--S--CH₂) 2H, 8.17-9.37 (m)(aromatics-H) 8H ppm

EXAMPLE 7 Production of 2-(methylthio-3-pyridyl)-benzoxazole ##STR10##

This compound is produced as in Example 1 from 2-mercaptobenzoxazole and3-picolyl chloride hydrochloride.

Colorless crystals melting at 88° C.; R_(f) =0.85 (CH₂ Cl₂ /CH₃ OH,85/15); Yield 11.1 g (46%) C₁₃ H₁₀ N₂ OS (242)

¹ H-NMR-spectrum (CDCl₃): δ=4.5 (s) (S--CH₂) 2H, 7.13-7.93 (m)(aromatics-H) 6H, 8.53 (d) (aromatics-H) 1H, 8.80 (s) (aromatics-H) 1Hppm

EXAMPLE 8 Production of 6-methyl-2-(methylthio-3-pyridyl)-benzoxazolehydrochloride ##STR11##

This compound is produced as in Example 1 from6-methyl-2-mercaptobenzoxazole and 3-picolyl chloride hydrochloride.

Colorless crystals melting at 182° to 183° C.; R_(f) =0.86 (CH₂ Cl₂/MeOH, 8/2, NH₃ -vapors); Yield 18.4 g (63%) C₁₄ H₁₃ ClN₂ OS (293)calculated: C 57.43 H 4.48 N 9.57 observed: C 57.49 H 4.57 N 9.57

¹ H-NMR-spectrum (D₂ O): δ=2.53 (s) (--CH₃) 3H, 5.00 (s) (S--CH₂) 2H,7.20-7.67 (m) (aromatics-H) 3H, 8.40 (m) (aromatics-H) 1H, 9.10 (m)(aromatics-H) 2H, 9.33 (s) (aromatics-H) 1H ppm

EXAMPLE 9 Production of 2-(methylthio-2-pyridyl)-benzoxazole oxalate##STR12##

This compound is produced as in Example 1 from 2-mercaptobenzoxazole and2-picolyl chloride hydrochloride. The oxalate is formed with half theequimolar quantity of oxalic acid in acetone.

Colorless crystals melting at 98° to 102° C.; R_(f) =0.4 (CH₂ Cl₂ /CH₃OH, 95/5); Yield 12.3 g (43%) C₁₄ H₁₁ N₂ O₃ S (287) calculated: C 58.53H 3.86 observed: C 58.46 H 3.89

¹ H-NMR-spectrum (CD₃ OD): δ=4.67 (s) (S--CH₂) 2H, 7.73-8.00 (m)(aromatics-H) 7H 8.50 (d) (aromatics-H) 1H ppm

EXAMPLE 10 Production of 2-(methylthio-3-pyridyl)-oxazolo(4,5-c)pyridine dihydrochloride ##STR13##

This compound is produced as in Example 1 from 2-mercapto-oxazolo(4,5-c)pyridine and 3-picolyl chloride hydrochloride.

Colorless crystals melting at 183° to 185° C.; R_(f) =0.77 (CH₂ Cl₂/MeOH, 8/2, NH₃ -vapors); Yield 17.4 g (55%) C₁₂ H₁₁ Cl₂ N₃ OS (316)calculated: C 45.58 H 3.51 N 13.29 S 10.14 observed: C 45.04 H 3.52 N12.91 S 10.05

¹ H-NMR-spectrum (D₂ O): δ=5.40 (s) (S--CH₂) 2H, 8.03-9.47 (m)(aromatics-H) 6H, 9.60 (s) (aromatics-H) 1H ppm

EXAMPLE 11 Production of phenyl-3-methylthiopyridine hydrochloride##STR14##

This compound is produced as in Example 1 from thiophenol and 3-picolylchloride hydrochloride.

Colorless crystals melting at 112° to 115° C.; R_(f) =0.72 (MeOH, NH₃-vapors); Yield 13.1 g (55%) C₁₂ H₁₂ ClNS (238) calculated: C 60.62 H5.09 N 5.89 S 13.48 Observed: C 60.52 H 5.03 N 5.88 S 13.49

¹ H-NMR-spectrum (D₂ O): δ=4.73 (s) (S--CH₂) 2H, 7.43-9.23 (m)(aromatics-H) 9H ppm

EXAMPLE 12 Production of 4-tolyl-3-methylthiopyridine hydrochloride##STR15##

This compound is produced as in Example 1 from p-methylthiophenol and3-picolyl chloride hydrochloride.

Colorless crystals melting at 148° to 149° C.; R_(f) =0.71 (MeOH, NH₃-vapors); Yield 11.8 g (47%) C₁₃ H₁₄ ClNS (252) calculated: C 62.02 H5.61 N 5.56 observed: C 62.08 H 5.55 N 5.61

¹ H-NMR-spectrum (D₂ O): δ=2.57 (s) (--CH₃) 3H, 4.67 (s) (S--CH₂) 2H,7.47 (s) (aromatics-H) 4H, 8.17-9.24 (m) (aromatics-H) 4H ppm

EXAMPLE 13 Production of 2-(pyridyl-4-methylthio)-pyrimidinehydrochloride ##STR16##

This compound is produced as in Example 1 from 2-mercaptopyridimine and4-picolyl chloride hydrochloride.

Colorless crystals melting at 170° to 173° C.; R_(f) =0.66 (MeOH, NH₃-vapors); Yield 10.3 g (43%) C₁₀ H₁₀ ClN₃ S (240) calculated: C 50.11 H4.20 N 17.53 S 13.37 observed: C 50.22 H 4.20 N 17.57 S 13.42

¹ H-NMR-spectrum (D₂ O): δ=5.10 (s) (S--CH₂) 2H, 7.53-9.43 (m)(aromatics-H) 7H ppm

EXAMPLE 14 Production of 4-chlorophenyl-3-methylthiopyridinehydrochloride ##STR17##

This compound is produced as in Example 1 from 4-chlorothiophenol and3-picolyl chloride hydrochloride.

Colorless crystals melting at 152° to 153° C.; R_(f) =0.58 (MeOH, NH₃-vapors); Yield 18.5 g (68%) C₁₂ H₁₁ Cl₂ NS (272) calculated: C 52.95 H4.07 N 5.15 observed: C 52.95 H 4.10 N 5.32

¹ H-NMR-spectrum (D₂ O): δ=4.73 (s) (S--CH₂) 2H, 7.47 (s) (aromatics-H)4H 8.20-9.30 (m) (aromatics-H) 4H ppm

EXAMPLE 15 Production of 2-(pyridyl-6-methyl-3-methylthio)-pyrimidinesuccinate ##STR18##

This compound is produced as in Example 1 from 2-mercaptopyrimidine and6-methyl-3-picolyl chloride hydrochloride.

Colorless crystals melting at 110° to 111° C.; R_(f) =0.63 (CH₂ Cl₂/MeOH, 95/5, NH₃ -vapors); Yield: 12.4 g (37%) C₁₅ H₁₇ N₃ O₄ S (335)calculated: C 53.72 H 5.11 N 12.53 observed: C 53.63 H 5.19 N 12.48

¹ H-NMR-spectrum (d₆ -DMSO): δ=2.43 (s) (--CH₂ --CH₂ --) (--CH₃) 7H,4.40 (s) (S--CH₂) 2H, 7.10-7.33 (m) (aromatics-H) 2H, 7.77 (d)(aromatics-H) 1H, 8.50 (s) (aromatics-H) 1H, 8.67 (d) (aromatics-H) 2Hppm.

EXAMPLE 16 Production of 3-methoxyphenyl-3-methylthiopyridinehydrochloride ##STR19##

This compound is produced as in Example 1 from 3-methoxy thiophenol and3-picolyl chloride hydrochloride.

Colorless crystals melting at 130° to 131° C.; R_(f) =0.75 (CH₂ Cl₂/MeOH, 95/5, NH₃ -vapors); Yield: 14.9 g (56%) C₁₃ H₁₄ ClNSO (267)

¹ H-NMR-spectrum (d₆ -DMSO): δ=3.73 (s) (--OCH₃) 3H, 4.50 (s) (S--CH₂)2H, 6.67-7.37 (m) (aromatics-H) 4H, 8.00 (dd) (aromatics-H) 1H, 8.50 (d)(aromatics-H) 1H, 8.87 (m) (aromatics-H) 2H ppm.

EXAMPLE 17 Production of 2-(pyridyl-2-chloro-3-methylthio)-pyrimiddine##STR20##

This compound is produced as in Example 1 from 2-mercaptopyrimidine and2-chloro-3-picolyl chloride hydrochloride.

Colorless crystals melting at 96° to 97° C.; R_(f) =0.69 (CH₂ Cl₂ /MeOH,9/1); Yield: 15.1 g (64%) C₁₀ H₈ ClN₃ S (238)

¹ H-NMR-spectrum (CDCl₃): δ=4.50 (s) (S--CH₂) 2H, 6.97 (t) (aromatics-H)1H, 7.13 (dd) (aromatics-H) 1H, 7.90 (d) (aromatics-H) 1H, 8.23 (d)(aromatics-H) 1H, 8.50 (d) (aromatics-H) 2H ppm

EXAMPLE 18 Production of 2-(pyridyl-3-methylthio)-benzimidazoledihydrochloride ##STR21##

This compound is produced as in Example 1 from 2-mercaptobenzimidazoleand 3-picolyl chloride hydrochloride.

Colorless crystals melting at 211° to 213° C.; R_(f) =0.62 (CH₂ Cl₂/MeOH, 95/5, NH₃ -vapors); Yield: 18.2 g (58%) C₁₃ H₁₃ Cl₂ N₃ S (314)

¹ H-NMR-spectrum (d₆ -DMSO): δ=5.17 (s) (S--CH₂) 2H, 7.20-8.17 (m)(aromatics-H) 5H, 8.63-8.87 (m) (aromatics-H) 2H, 9.10 (s) (aromatics-H)1H ppm

EXAMPLE 19 Production of 2-(pyridyl-3-methylthio)-4,5-diphenyl oxazolehydrochloride ##STR22##

This compound is produced as in Example 1 from2-mercapto-4,5-diphenyloxazole and 3-picolyl chloride hydrochloride.

Colorless crystals melting at 156° to 157° C.; R_(f) =0.62 (CH₂ Cl₂/MeOH, 95/5, NH₃ -vapors); Yield: 17.9 g (47%) C₂₁ H₁₇ ClN₂ OS (381)calculated: C 66.22 H 4.50 N 7.35 observed: C 66.23 H 4.50 N 7.47

¹ H-NMR-spectrum (d₄ -MeOH): δ=4.73 (s) (S--CH₂) 2H, 7.20-7.67 (m)(aromatics-H) 10H, 8.13 (t) (aromatics-H) 1H, 8.73-9.0 (m) (aromatics-H)2H, 9.10 (s) (aromatics-H) 1H ppm

EXAMPLE 20 Production of 2-(pyridyl-3-methylthio)-quinolinedihydrochloride ##STR23##

This compound is produced as in Example 1 from 2-mercaptoquinoline and3-picolyl chloride hydrochloride.

Colorless crystals melting at 173° to 175° C.; R_(f) =0.71 (CH₂ Cl₂/MeOH, 95/5, NH₃ -vapors); Yield: 16.9 g (52%) C₁₅ H₁₄ Cl₂ N₂ S (325)calculated: C 55.39 H 4.34 S 9.86 observed: C 55.26 H 4.36 S 9.36

¹ H-NMR-spectrum (D₂ O): δ=5.30 (s) (S--CH₂) 2H, 7.70-9.70 (m)(aromatics-H) 10H ppm.

EXAMPLE 21 Production of 2-(pyridyl-3-methylthio)-1-methylimidazoledihydrochloride ##STR24##

This compound is produced as in Example 1 from2-mercapto-1-methylimidazole and 3-picolyl chloride hydrochloride.

Colorless crystals melting at 187° to 189° C.; R_(f) =0.43 (CH₂ Cl₂/MeOH, 95/5, NH₃ -vapors); Yield: 12.0 g (43%) C₁₀ H₁₅ Cl₂ N₃ S (280)calculated: C 42.86 H 5.40 N 15.00 observed: C 43.08 H 4.77 N 15.03

¹ H-NMR-spectrum (D₂ O): δ=4.43 (s) (N--CH₃) 3H, 5.13 (s) (S--CH₂) 2H,8.00-9.53 (m) (aromatics-H) 6H ppm.

EXAMPLE 22 Production of 2-(pyridyl-3-methylthio-6-chloro)-pyrimidine##STR25##

This compound is produced as in Example 1 from 2-mercaptopyrimidine and6-chloro-3-picolyl chloride hydrochloride.

Colorless crystals melting at 89° to 90° C.; R_(f) =0.68 (CH₂ Cl₂ /MeOH,9/1); Yield: 10.0 g (42%) C₁₀ H₈ ClN₃ S (238)

¹ H-NMR-spectrum (CDCl₃): δ=4.33 (s) (S--CH₂) 2H, 7.00 (t) (aromatics-H)1H, 7.20 (d) (aromatics-H) 1H, 7.77 (dd) (aromatics-H) 1H, 8.50 (m)(aromatics-H) 3H ppm.

EXAMPLE 23 Production of4-(pyridyl-3-methylthio)-1-H-pyrazolo-(3,4-d)-pyrimidine ##STR26##

This compound is produced as in Example 1 from4-mercapto-1-H-pyrazolo-(3,4-d)-pyrimidine and 3-picolyl chloridehydrochloride.

Colorless crystals melting at 148° to 149° C.; R_(f) =0.54 (CH₂ Cl₂/MeOH, 9/1); Yield: 16.0 g (66%) C₁₁ H₉ N₅ S (243) calculated: C 54.31 H3.73 N 28.79 observed: C 54.27 H 3.77 N 28.75

¹ H-NMR-spectrum (d₆ -DMSO): δ=4.70 (s) (S--CH₂) 2H, 7.33 (dd)(aromatics-H) 1H, 8.27 (s) (aromatics-H) 1H, 8.50 (d) (aromatics-H) 1H,8.73 (s) (aromatics-H) 1H, 8.83 (s) (aromatics-H) 1H, 14.13 (s) (N--H)1H (exchangeable for D₂ O) ppm.

EXAMPLE 24

Production of soft gelatin capsules containing the active principleaccording to the invention, for example2-(pyridyl-3-methylthio)-pyrimidine hydrochloride:

Composition

    ______________________________________    2-(pyridyl-3-methylthio)-pyrimidine hydrochloride                               100.0 mg    Rape oil                   281.0 mg    Beeswax                    2.0 mg    Partially hydrogenated vegetable oil                               8.0 mg    Soy lecithin               8.0 mg    3-ethoxy-4-hydroxybenzaldehyde                               1.0 mg    Total weight of capsule filling                               400.0 mg    ______________________________________

The substances are mixed, homogenized and processed in the usual way toform soft gelatin capsules.

EXAMPLE 25

Production of dosing aerosols containing the active principle accordingto the invention, for example 2-(pyridyl-3-methylthio)-pyrimidinehydrochloride:

Composition

    ______________________________________    2-(pyridyl-3-methylthio)-pyrimidine hydrochloride                               10.0 mg    Sorbitan trioleate          0.5 mg    Difluoromethane            35.5 mg    Dichlorotetrafluoroethane  25.0 mg    Total dose per spray       71.0 mg    ______________________________________

The substances are dissolved cold and 10 g of solution are introducedinto a suitable pressurized-gas pack.

EXAMPLE 26

Production of ampoules containing the active principle according to theinvention, for example 2-(pyridyl-3-methylthio)-pyrimidinehydrochloride:

Composition

    ______________________________________    2-(pyridyl-3-methylthio)-pyrimidine hydrochloride                               100.0 mg    Polyethylene glycol 300    630.0 mg    1,2-propane diol           735.0 mg    α-tocopherol          1.0 mg    Disodium hydrogen phosphate                                4.0 mg    Sodium dihydrogen phosphate                                20.0 mg    Water for injection purposes                               610.0 mg    Total weight of filling    2100.0 mg    ______________________________________

The substances are dissolved and the solution obtained is processed inthe usual way to form 2 ml ampoules.

What is claimed is:
 1. A method for eliciting a bronchosecretolytic ormucolytic response in a mammalian organism in need of such treatment,comprising administering to such organism a bronchosecretolytically ormucolytically effective amount of a thiomethyl pyridine compound havingthe formula: ##STR27## wherein Q is an imidazolyl radical or asubstituted imidazolyl radical attached to the sulfur atom through aring carbon, wherein the substitution includes a halogen, lower alkylhaving from 1 to 4 carbon atoms or lower alkoxy having from 1 to 4carbon atoms, R' is lower alkyl having 1 to 4 carbon atoms, halogen oraminoalkyl having from 1 to 4 carbon atoms and n is 0 or an integer offrom 1 to 4, or a pharmaceutically effective salt thereof.
 2. A methodfor reducing the viscosity of sputum in a mammalian organism in need ofsuch treatment, comprising administering to such organism abronchosecretolytically or mucolytically effective amount of athiomethyl pyridine compound having the formula: ##STR28## wherein Q isan imidazolyl radical or a substituted imidazolyl radical attached tothe sulfur atom through a ring carbon, wherein the substitution includesa halogen, lower alkyl having from 1 to 4 carbon atoms or lower alkoxyhaving from 1 to 4 carbon atoms, R' is lower alkyl having 1 to 4 carbonatoms, halogen or aminoalkyl having from 1 to 4 carbon atoms and n is 0or an integer of from 1 to 4, or a pharmaceutically effective saltthereof.
 3. A method for treating acute or chronic respiratory diseasein a mammalian organism in need of such treatment, comprisingadministering to such organism a therapeutically effective amount of athiomethyl pyridine compound having the formula: ##STR29## wherein Q isan imidazolyl radical or a substituted imidazolyl radical attached tothe sulfur atom through a ring carbon, wherein the substitution includesa halogen, lower alkyl having from 1 to 4 carbon atoms or lower alkoxyhaving from 1 to 4 carbon atoms, R' is lower alkyl having 1 to 4 carbonatoms, halogen or aminoalkyl having from 1 to 4 carbon atoms and n is 0or an integer of from 1 to 4, or a pharmaceutically effective saltthereof.
 4. A method for treating bronchial illness in a mammalianorganism, comprising administering to such organism a therapeuticallyeffective amount of a thiomethyl pyridine compound having the formula:##STR30## wherein Q is an imidazolyl radical or a substituted imidazolylradical attached to the sulfur atom through a ring carbon, wherein thesubstitution includes a halogen, lower alkyl having from 1 to 4 carbonatoms or lower alkoxy having from 1 to 4 carbon atoms, R' is lower alkylhaving 1 to 4 carbon atoms, halogen or aminoalkyl having from 1 to 4carbon atoms and n is 0 or an integer of from 1 to 4, or apharmaceutically effective salt thereof.
 5. A method according to claim1, wherein said method includes administration of said thiomethylpyridine compound in oral dosage form.
 6. A method as claimed in claim 1wherein said method includes parenteral administration of saidthiomethyl pyridine compound.